4-Hydroxynonenal (HNE) is one of the major products of oxidative decomposition of omega-3 and omega-6 polyunsaturated fatty acids of membrane phospholipids. HNE was originally considered to be an ultimate mediator of toxic effects elicited by oxidative stress. Experimental and clinical evidences now suggest that HNE can also act as a biological signal in normal and pathological conditions. In the last few years we accumulated evidences on the role played by HNE in the differentiation induction of leukemic cells, at concentrations similar to those detected in normal cells and plasma. In this mini-review, we would like to offer recent literature data supporting the hypothesis that HNE can act as a signal molecule able to modulate biological events, such as cell proliferation and differentiation.